We have demonstrated a temporal relationship between changes in the acid-base balance of man and animals and erythropoietin (Ep) production. One can dramatically reduce the measurable Ep during "hypoxic" stresses by preventing the changes in pH and/or pCO2 which occur with hypoxia. These effects do not depend solely on alterations in the affinity of hemoglobin for O2 since we have also demonstrated that one can produce highly significant increases in the affinity of hemoglobin for O2 with cyanate without demonstrable plasma Ep increase. In the cyanated rat the red cell mass is increased hence there has been increased red cell production in the absence of a measurable increase in plasma Ep. We will address two basic questions in this research. These are: (1) Is "hypoxia" the sole regulator of Ep production or are there additional regulators i.e., pH and/or pCO2? (2) Is red cell production totally on Ep or are there other regulators? The mechanism whereby hypercarbia and/or acidemia lead to a suppression of Ep production will be investigated by measurements of renal blood flow and cardiac output as well as determining the influence of pH on the binding of Ep to red cell membranes. Several models exist in which the Ep response differs from that predicted and 2 of these will be studied viz the Ep response of both the CAF1 mouse and the hypophysectomized rat to hypoxia. The second major area of investigation will be directed toward defining the role of Ep in red cell production. Cyanated rats with implanted plasma clot diffusion chambers will be used to determine if BFU-E and CFU-E grow in animals whom we have increased red cell production without measurable plasma levels of Ep. These cells will then be grown in vitro in order to demonstrate whether or not they are Ep dependent. These studies have direct clinical relevance in our understanding of red cell production in patients with a number of medical diseases which result in either anemia or polycythemia. Specifically, we propose to relate the development of polycythemia in patients with COPD to their arterial pCO2 levels.